Morphine formulations

ABSTRACT

Provided herein, generally, are pharmaceutical formulations, e.g., injectable pharmaceutical formulations with improved stability, comprising morphine sulfate or a hydrate thereof, and methods of producing and using the same. Also provided herein are kits comprising the formulations, e.g., injectable morphine formulations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/272,108, filed on Feb. 11, 2019, which is a continuation of U.S.patent application Ser. No. 14/887,803, filed on Oct. 20, 2015 (now U.S.Pat. No. 10,213,424), which is a continuation of U.S. patent applicationSer. No. 14/715,277, filed May 18, 2015 (now U.S. Pat. No. 9,192,608);which is a divisional application of U.S. patent application Ser. No.14/207,245, filed Mar. 12, 2014 (now U.S. Pat. No. 9,072,781), whichclaims the benefit of U.S. Provisional Application No. 61/785,218, filedMar. 14, 2013, all of which are hereby incorporated herein by referencein their entireties.

BACKGROUND OF THE INVENTION

Morphine is a narcotic pain reliever widely used to treat moderate tosevere pain. It is generally thought that morphine acts as an agonist atthe μ-opioid receptor primarily and also the κ- and δ-opioid receptorsof the central nervous system. By acting on one or more of thesereceptors, morphine can cause analgesia and anesthesia as a result of areceptor-mediated central action on pain perception. In addition toanalgesia and anesthesia, morphine can provide widely diverse effectsincluding alterations in mood, euphoria and/or feelings of relaxation,dysphoria, drowsiness, decreased gastrointestinal motility, respiratorydepression, nausea, vomiting and alterations of the endocrine andautonomic nervous system.

Morphine has been used for a variety of clinical indications. Someexamples of such indications include analgesia for treatment of acuteand chronic pain due to, for example, cancer or post-operative surgery,anesthesia during surgery and to allay anxiety during acute pulmonaryedema. Several delivery routes have been utilized for administeringmorphine. These routes include oral, rectal, parenteral (injectable) andbuccal administration.

SUMMARY OF THE INVENTION

Provided herein are pharmaceutical formulations, e.g., injectablepharmaceutical formulations, comprising morphine sulfate or a hydratethereof, methods of producing and using the same, and kits comprisingthe formulations, e.g., injectable morphine formulations.

In one aspect, provided herein is a pharmaceutical formulation, e.g., aninjectable pharmaceutical formulation, comprising: (a) morphine, or asalt thereof, or a hydrate thereof; (b) an isotonic agent; (c) abuffering agent with anti-oxidative properties; (d) a chelating agent;(e) a complement to a chelating agent; and (f) water.

In one embodiment of the formulation, the morphine, or a salt thereof,or a hydrate thereof, is selected from anhydrous morphine, morphinehydrochloride, morphine sulfate, morphine tartrate, morphine citrate,morphine acetate, morphine methobromide, morphine hydrobromide, morphinehydroiodide, morphine lactate and morphine bitartrate. In anotherembodiment, the morphine, or a salt thereof, or a hydrate thereof, isselected from morphine sulfate pentahydrate or morphine hydrochloride.

In another embodiment, the isotonic agent is selected from sodiumchloride, calcium chloride, potassium chloride, sodium bicarbonate,sodium lactate, Ringer's solution, dextrose, lactose, mannitol, glucose,glycerine, dextran, Normosol R, saline, Hartmann's solution, andmixtures and combinations thereof. In another embodiment, the isotonicagent is sodium chloride.

In another embodiment, the buffering agent is a di-carboxylic ortri-carboxylic acid. In another embodiment, the buffering agent iscitric acid, iso citric acid, aconitic acid, trimesic acid,propane-1,2,3-tricarboxylic acid, fumaric acid, oxalic acid, maleicacid, malonic acid, glutaric acid, succinic acid or tartaric acid, orhydrates thereof. In another embodiment, the buffering agent is citricacid. In another embodiment, the formulation further comprises aconjugate base to the buffering agent. In another embodiment, thebuffering agent is in an amount which provides a molar ratio of morphineto the buffering agent from about 0.4 to about 1.3. In anotherembodiment, the buffering agent is in an amount which provides a molarratio of morphine to the buffering agent from about 0.4 to about 0.8. Inanother embodiment, the buffering agent forms a buffer comprised ofanhydrous citric acid and hydrates thereof and anhydrous sodium citrateand hydrates thereof. In another embodiment, the buffering agent is inan amount sufficient to provide a pH of from about 2.5 to about 6.5 tothe formulation. In another embodiment, the buffering agent is in anamount sufficient to provide a pH of from about 4.5 to about 5.5 to theformulation. In another embodiment, the buffering agent is in an amountsufficient to provide a pH of about 5 to the formulation.

In another embodiment, the chelating agent is selected from edetic acid,ethylene glycol tetraacetic acid, ethylenediamine, diethylene triaminepentaacetic acid, N-(hydroxyethyl) ethylenediaminetriacetic acid,aminotriacetic acid, 2,3-dimercapto-1-propanesulfonic acid,dimercaptosuccinic acid, dimercaprol,1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, salts andhydrates thereof. In another embodiment, the chelating agent is edeticacid. In another embodiment, the complement to chelating agent is acalcium salt. In another embodiment, the complement to chelating agentis calcium chloride dihydrate.

In another embodiment, the formulation provides a unit dose of morphine,or a salt thereof, or a hydrate thereof, from about 2 mg/mL to about 15mg/mL. In another embodiment, the formulation provides a unit dose ofmorphine, or a salt thereof, or a hydrate thereof, from about 2 mg/mL toabout 10 mg/mL.

In certain embodiments, the formulation provided herein comprises per mL(a) from about 2 mg to about 15 mg of morphine sulfate pentahydrate; (b)an isotonic agent; (c) a buffering agent in an amount which provides amolar ratio of morphine sulfate to the buffering agent from about 0.4 toabout 1.3 and is in an amount sufficient to provide a pH of about 5 tothe formulation; (d) a chelating agent; (e) a complement to a chelatingagent; and (f) water.

In some embodiments, the formulation provided herein is stable at 80° C.for at least 14 days. In some embodiments, the formulation providedherein is stable at 40° C./75% RH for at least three months. In someembodiments, the formulation provided herein is stable at 25° C./60% RHfor at least 12 months.

In some embodiments, the formulation provided herein is stored in aglass or plastic container which is stored in a secondary containerhaving reduced permeability to oxygen and further comprising an oxygenscavenger. In certain instances, the formulation provided herein isstable at 40° C./75% RH for at least six months. In certain instances,the formulation provided herein is stable at 25° C./60% RH for at least24 months.

Also provided herein are injectable formulations comprising per mL: (a)from about 2 mg to about 10 mg of morphine sulfate or a hydrate thereof;(b) sodium chloride; (c) a buffering system comprised of a bufferingagent in an amount which provides a molar ratio of morphine sulfate tothe buffering agent from about 0.4 to about 1.3 and is in an amountsufficient to provide a pH of about 5 to the formulation and a conjugatebase to the buffering agent; (d) disodium edetate or a hydrate thereof;(e) calcium chloride or a hydrate thereof; and (f) water for injection.

In certain embodiments, the formulation comprises per mL: (a) from about4 mg and 10 mg of morphine sulfate or a hydrate thereof; (b) sodiumchloride; (c) a buffering agent in an amount which provides a molarratio of morphine sulfate to the buffering agent from about 0.4 to 0.8and is in an amount sufficient to provide a pH of about 5 to theformulation; (d) disodium edetate or a hydrate thereof; (e) calciumchloride or a hydrate thereof; and (f) water for injection.

In one embodiment of the formulation, the buffering agent is also ananti-oxidative agent. In another embodiment of the formulation, thebuffering agent forms a buffer comprised of citric acid monohydrate andsodium citrate dihydrate.

In another embodiment, the formulation is stable at 80° C. for at least14 days. In some embodiments, the formulation provided herein is stableat 40° C./75% RH for at least three months. In some embodiments, theformulation provided herein is stable at 25° C./60% RH for at least 12months.

In another aspect, provided herein is a pharmaceutical formulation,e.g., an injectable pharmaceutical formulation, comprising per mL: (a)from about 2 mg to about 10 mg of morphine sulfate pentahydrate; (b)from about 7 mg to about 9 mg of sodium chloride; (c) from about 2 mg toabout 4 mg of sodium citrate dehydrate; (d) from about 0.7 to about 1.2mg of citric acid monohydrate; (e) from about 0.1 to about 0.15 mg ofdisodium edetate dihydrate; (f) from about 0.04 to about 0.06 mg calciumchloride dihydrate; and (g) water for injection.

In one embodiment, the formulation comprises per mL (a) about 2 mgmorphine sulfate pentahydrate; (b) about 8.4 mg of sodium chloride; (c)about 2.3 mg of sodium citrate dehydrate; (d) about 0.74 mg of citricacid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f)about 0.053 mg calcium chloride dihydrate; and (g) water for injection.

In another embodiment, the formulation comprises per mL (a) about 4 mgmorphine sulfate pentahydrate; (b) about 8.4 mg of sodium chloride; (c)about 2.3 mg of sodium citrate dehydrate; (d) about 0.74 mg of citricacid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f)about 0.053 mg calcium chloride dihydrate; and (g) water for injection.

In another embodiment, the formulation comprises per mL (a) about 5 mgmorphine sulfate pentahydrate; (b) about 7.5 mg of sodium chloride; (c)about 3.45 mg of sodium citrate dehydrate; (d) about 1.11 mg of citricacid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f)about 0.053 mg calcium chloride dihydrate; and (g) water for injection.

In another embodiment, the formulation comprises per mL (a) about 8 mgmorphine sulfate pentahydrate; (b) about 7.5 mg of sodium chloride; (c)about 3.45 mg of sodium citrate dehydrate; (d) about 1.11 mg of citricacid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f)about 0.053 mg calcium chloride dihydrate; and (g) water for injection.

In another embodiment, the formulation comprises per mL (a) about 10 mgmorphine sulfate pentahydrate; (b) about 7.5 mg of sodium chloride; (c)about 3.45 mg of sodium citrate dehydrate; (d) about 1.11 mg of citricacid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f)about 0.053 mg calcium chloride dihydrate; and (g) water for injection.

In various embodiments, the formulation is stored in a glass or plasticcontainer. In various other embodiments, the glass or plastic containeris a prefilled syringe or a vial. In various other embodiments, theformulation is stored in a glass container which is stored in asecondary container having reduced permeability to oxygen and furthercomprising an oxygen scavenger. In certain instances, the formulationprovided herein is stable at 40° C./75% RH for at least six months. Incertain instances, the formulation provided herein is stable at 25°C./60% RH for at least 24 months.

In another aspect, provided herein is a method of reducing pain in asubject, comprising: administering to the subject a morphinepharmaceutical formulation, e.g., an injectable pharmaceuticalformulation comprising per mL (a) from about 2 mg to about 10 mg ofmorphine sulfate or a hydrate thereof; (b) sodium chloride; (c) abuffering agent in an amount which provides a molar ratio of morphinesulfate to the buffering agent from about 0.4 to about 1.3 and is in anamount sufficient to provide a pH of about 5 to the formulation; (d)disodium edetate dihydrate; (e) calcium chloride dihydrate; and (f)water.

In another aspect, provided herein is a method of reducing adverseeffects of a injectable morphine pharmaceutical formulation comprisingdisodium edetate dihydrate, the method comprising the addition ofcalcium chloride dihydrate to the injectable morphine pharmaceuticalformulation wherein the formulation comprises per mL: (a) from about 2mg to about 10 mg of morphine sulfate or a hydrate thereof; (b) sodiumchloride; (c) a buffering agent in an amount which provides a molarratio of morphine sulfate to the buffering agent from about 0.4 to about1.3 and is in an amount sufficient to provide a pH of about 5 to theformulation; (d) disodium edetate dihydrate; (e) calcium chloridedihydrate; and (f) water.

In another aspect, provided herein is a kit comprising (a) a pre-filledsyringe comprising a morphine formulation described herein; and (b) asecondary container having reduced permeability to oxygen and furthercomprising an oxygen scavenger.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings:

FIG. 1: Total impurities results by UPLC for 10 mg/mL morphine sulfatesolution having pH 2.5, 4.0, 5.0 or 6.5 prepared under inert (nitrogen)or air conditions at storage condition at 80° C. for 6 days.

FIG. 2: Total impurities results by UPLC for 10 mg/mL morphine sulfatesolution having pH 2.5, 4.0, 5.0 or 6.5 prepared under inert (nitrogen)or air conditions stored at accelerated conditions (40° C./75% RH) for 4weeks.

FIG. 3: Morphine content results by UPLC for 10 mg/mL morphine sulfatesolution having pH 2.5, 4.0, 5.0 or 6.5 prepared under inert (nitrogen)conditions at storage condition of 80° C. for 6 days.

FIG. 4: Total impurities results by UPLC for 2 mg/mL morphinesulfate/NaCl formulation stored 6 months at accelerated conditions (40°C./75% RH) for different process configurations [Oxygen: N2 (fullyinert), SemiN2 (partially inert), Air (Non-inert) and Terminalsterilization: A (autoclaved), NonA (no autoclave)].

FIG. 5: Pseudomorphine content by UPLC for Morphine sulfate/NaClformulation 2, 5 and 10 mg/mL, fully inerted and autoclaved stored ataccelerated conditions (40° C./75% RH) for 6 months.

FIG. 6: Relative Retention time 0.16 Unknown Impurity content by UPLC ofMorphine sulfate/NaCl formulation 2, 5 and 10 mg/mL, fully inerted andautoclaved stored at 40° C./75% RH) for 6 months.

FIG. 7: Pseudomorphine content by UPLC of various 2 mg/mL Morphinesulfate formulations as described in Example 3, fully inerted andnon-autoclaved stored at 80° C. for 14 days.

FIG. 8: Total impurities content by UPLC of various 2 mg/mL Morphinesulfate formulations as described in Example 3, fully inerted andnon-autoclaved stored at 80° C. for 14 days.

FIG. 9: Comparison of two 2 mg/mL Morphine sulfate formulations(+chelating agents and pH adjusted; +chelating agents and +buffersystem), fully inerted and non-autoclaved stored at 80° C. for 14days—pH assay.

FIG. 10: Pseudomorphine content by UPLC of 2 mg/mL Morphine sulfateformulation from Example 4 stored 6 months at accelerated conditions(40° C./75% RH).

FIG. 11: Schematic of exemplary packaging system embodiments with oxygenabsorber in a sachet (a), in the lid (b), in a canister (c) andpositioned on the primary packaging (d).

FIG. 12: Drawing of a exemplary syringe and secondary packagingembodiment where a secondary packaging includes a first compartment toreceive a syringe barrel and second compartment to receive a plunger rodseparate and detached from the syringe barrel.

DETAILED DESCRIPTION OF THE INVENTION Morphine Formulations forInjectable Administration

Provided herein are stable morphine formulations for injectableadministration. These morphine formulations described herein are usefulfor the treatment and management of pain as well as anesthesia. Thecompositions are advantageous over conventional formulations of morphineranging from increased stability, reduction of side effects andcomplementation to certain types of packaging.

The injectable morphine formulations described herein are stable overtime (at least 2 years) when stored in a glass or plastic container. Afeature of the formulations provided herein is that, under suitablestorage, the level of total impurities is low (e.g., total impurities nomore than 1.5% w/w of the Morphine sulfate assay, or total impurities nomore than 0.5% w/w of the Morphine sulfate assay, over the period ofshelf life). In specific embodiments, the pseudomorphine level, which isthe main degradation product due to oxidation, is maintained under 0.2%all along the shelf life (i.e., no more than 0.2% w/w of the Morphinesulfate quantity).

As used herein, “morphine” refers to the base opioid alkaloid having thestructure:

(5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol C₁₇H₁₉NO₃

or its salts, hydrates, solvates, derivatives or polymorphs thereof.

Suitable morphine forms for the formulations described herein includethe free base, the organic and inorganic salts, isomers, isomer salts,solvates, polymorphs, complexes etc. Morphine is traditionally isolatedand prepared from the opium poppy (Papaver somniferum). U.S. Pat. Nos.1,048,712; 2,715,627; and 6,054,584 disclose exemplary methods for theisolation and preparation of morphine.

Anhydrous morphine or various morphine salts or hydrates arecontemplated for use in the formulations provided herein, for example,morphine hydrochloride, morphine sulfate, morphine tartrate, morphinecitrate, morphine methobromide, morphine hydrobromide, morphinehydroiodide, morphine lactate, morphine bitartrate, morphine tannate,morphine phosphate, morphine ascorbate and morphine acetate. In certainembodiments, the morphine, or a salt thereof, or a hydrate thereof usedherein, is selected from morphine sulfate pentahydrate or morphinehydrochloride. In some embodiments, the morphine, or a salt thereof, ora hydrate thereof used herein is morphine hydrochloride. In otherembodiments, the morphine, or a salt thereof, or a hydrate thereof usedherein is morphine sulfate pentahydrate. Morphine sulfate pentahydratehas the following structural formula:

(5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol sulfatepentahydrate (C₁₇H₁₉NO₃)₂.H₂SO₄.5H₂O

In some embodiments, morphine is present in a concentration of about 1mg/mL to about 15 mg/mL of the morphine formulation. In some otherembodiments, morphine is present in a concentration about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL or about 15 mg/mLof the morphine formulation. In certain embodiments, morphine is presentin a concentration of about 2 mg/mL of the morphine formulation. Incertain embodiments, morphine is present in a concentration of about 1mg/mL of the morphine formulation. In certain embodiments, morphine ispresent in a concentration of about 4 mg/mL of the morphine formulation.In certain embodiments, morphine is present in a concentration of about5 mg/mL of the morphine formulation. In certain embodiments, morphine ispresent in a concentration of about 8 mg/mL of the morphine formulation.In certain embodiments, morphine is present in a concentration of about10 mg/mL of the morphine formulation. In certain embodiments, morphineis present in a concentration of about 15 mg/mL of the morphineformulation.

To provide the particular features described above, in one aspect, themorphine formulations herein comprise the following components orexcipients: an isotonic agent, a buffering system, a chelating agent,and a complement to the chelating agent. These components impartimproved stability and reduced degradation of morphine as compared toknown marketed morphine products (see Example 7).

pH of the Morphine Formulations

Typical marketed injectable formulations of morphine vary in pH fromabout 2.5 to 6.5. Thus, in certain embodiments, morphine formulationsdescribed herein are contemplated to have a pH from about 2.5 to 6.5.However surprisingly, as shown in Example 1, maintaining the pH ofmorphine formulations close to 5 provides increased stability ofmorphine and enhances shelf life. Specifically, the morphine formulationat pH 5.0 showed lower total impurities during storage than other pHvalues. Accordingly, in some embodiments, provided herein are morphineinjectable formulations having a pH of from about 4.5 to about 5.5, orfrom about 4.7 to about 5.2, or about 5. In certain embodiments, themorphine formulations described herein have a pH of about 5.0. Inalternative embodiments, the morphine formulations described herein havea pH of about 4.0 which, according to Example 1, shows better stabilitythan at other pH except for pH 5.0. The pH of the morphine formulationsdescribed herein are, in some embodiments, obtained via a buffer systemin the formulation. In other embodiments, the desired pH is obtained byadjustment of the formulation with adjustment with an acid and base(e.g., HCl or H₂SO₄ and NaOH).

Isotonic Agents

Isotonic agents, also known as tonicity or tonicity-adjusting agents,increase isotonic compatibility with physiological environments with theinjected morphine formulation. In some embodiments, the addition of anisotonic agent(s) provides an osmolality that is similar to or equal toblood osmolality. In other embodiments, the addition of an isotonicagent(s) provides an osmolality of about 280 to about 310 mOsm/Kg.Isotonic agents include, but are not limited to electrolytes andsaccharides (e.g., dextrose, lactose, mannitol, glucose, dextran,ammonium chloride, sodium chloride, calcium chloride, potassiumchloride, sodium bicarbonate, sodium lactate, Ringer's solution,Lactated Ringer's solution, Normosol R, saline, Hartmann's solution, andmixtures and combinations thereof). In some embodiment, the isotonicagent is a Ringer's solution. In other embodiments, an isotonic agent isselected from mannitol, sodium chloride, glycerine, sodium lactate,potassium chloride, and calcium chloride. In further embodiments, theisotonic agent is sodium chloride. In certain instances, the sodiumchloride is present at a concentration from about 5 to about 9 mg/mL inthe morphine formulation. In certain instances, the sodium chloride ispresent at a concentration from about 7 to about 9 mg/mL in the morphineformulation. In other instances, the sodium chloride is present at aconcentration at about 7.5 mg/mL in the morphine formulation. In yetother instances, the sodium chloride is present at a concentration atabout 8.4 mg/mL in the morphine formulation. Concentrations ofadditional or other isotonic agents are obtained by determining theosmolality brought about by the morphine and other excipients in theformulation and calculating the concentration needed by the isotonicagent to provide an osmolality that is similar to or equal to bloodosmolality and/or an osmolality of about 280 to about 310 mOsm/Kg.

Buffering System

The buffering system in the morphine formulations described hereinfunction to keep the pH constant throughout the formulations' shelf lifeas well as providing anti-oxidant properties to prevent degradation. Afeature of the buffer system, not present in existing morphineformulations, is that the buffering agent concentration is connected tothe concentration of the active substance, morphine. Otherwise, anincrease in the buffer concentration may cause an increase in painperceived by the subject during and/or after injection of the morphineformulation. Hence, in some embodiments, the molar ratio of morphine tothe buffering agent from about 0.4 to about 1.3 for a range of morphineconcentrations between about 10 mg/mL and about 2 mg/mL. In otherembodiments, molar ratio of morphine to the buffering agent from about0.4 to about 0.8 for a range of morphine concentrations between about 10mg/mL and about 4 mg/mL. The buffer ratios ensure the correct pHproperties and the stability of the solution within the formulation'sshelf life.

The buffering system comprises two components: a di-carboxylic ortri-carboxylic acid as a buffering agent and its conjugate base. Acidswith more than one carboxylic acid group can act as chelating moietiesfor multivalent cations. Suitable acids include, but are not limited to,citric acid, iso citric acid, aconitic acid, trimesic acid,propane-1,2,3-tricarboxylic acid, fumaric acid, oxalic acid, maleicacid, malonic acid, glutaric acid, succinic acid or tartaric acid. Insome embodiments, the morphine formulations described herein comprise adi-carboxylic or tri-carboxylic acid and its conjugate base. In otherembodiments, the morphine formulations described herein comprise abuffering agent selected from citric acid, iso citric acid, aconiticacid, trimesic acid, propane-1,2,3-tricarboxylic acid, fumaric acid,oxalic acid, maleic acid, succinic acid or tartaric acid. In furtherembodiments, the morphine formulations described herein comprise citricacid. In yet further embodiments, the buffering system of the morphineformulations described herein comprises citric acid and sodium citratein their anhydrous or hydrates forms. In certain instances, the morphineformulations described herein comprise citric acid monohydrate andsodium citrate dihydrate.

The two components of the buffer system can be varied to produce adesired pH. For example, citric acid can be increased while sodiumcitrate is decreased to lower the pH and conversely, citric acid can bedecreased while sodium citrate is increased to raise the desired pH.Thus, by adjusting the concentrations of both components, pH values from2.5 to 6.5 can be obtained. For the morphine formulations describedherein, in some embodiments, the buffer system is in an amountsufficient to provide a pH of from about 2.5 to about 6.5 to theformulation. In other embodiments, the buffer system is in an amountsufficient to provide a pH of about 5.0. Exemplary buffer concentrationsare described in more detail in Example 4.

Chelating Agents

Chelating agents, or complexing agents or sequestering agents complex orchelate metal ions and are useful in pharmaceutical formulations bycomplexing to metal ions such as Zn²⁺, Cu²⁺, Mg²⁺, etc. that are presentin containers. The presence of such metal ions can initiate reactionssuch as oxidation reactions that would indirectly lead to thedegradation of the active drug substance. Exemplary chelating agents areEDTA (ethylenediaminetetraacetic acid or edetic acid) and EGTA (ethyleneglycol tetraacetic acid) and their salts and hydrates thereof. Otherchelating agents include, but are not limited to ethylenediamine, DPTA(pentetic or diethylene triamine pentaacetic acid), HEDTA(N-(hydroxyethyl) ethylenediaminetriacetic acid), NTA (aminotriaceticacid), DMPS (2,3-dimercapto-1-propanesulfonic acid), DMSA(dimercaptosuccinic acid), BAL (dimercaprol), BAPTA(1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid), and theirsalts and hydrates thereof, porphyrins and the like. In someembodiments, the chelating agent is anhydrous EDTA or its salt orhydrated form. In some instances, the EDTA is disodium EDTA, calciumdisodium EDTA, trisodium EDTA, tetrasodium EDTA, dipotassium EDTA,tripotassium EDTA, or the like. In certain instances, the EDTA isdisodium EDTA. In some instances, the EDTA is present at a concentrationat about 0.1 mg/mL in the morphine formulation. In some instances, theEDTA is present at a concentration at about 0.111 mg/mL in the morphineformulation. In other embodiments, the chelating agent is anhydrous EGTAor its salt or hydrated form. In further embodiments, the chelatingagent is an EDTA/EGTA combination.

Complement to Chelating Agent

In addition to chelating metal ions that are present in pharmaceuticalformulation containers, chelating agents can also chelate important ionsin the body and interfere with physiological processes. For example,EDTA chelates serum Ca′ which can impair the blood coagulation pathway,calcium metabolism, signal transduction and, in certain amounts, cancause hypocalcaemia. To overcome the detrimental effects of chelatingagents in the morphine formulations described herein, a complement tochelating agent is added, in some embodiments. Complements to chelatingagent are certain agents which prevent chelation of endogenous metalions such as calcium. In a non-limiting example, calcium chlorideinteracts with EDTA and prevents chelation of Ca²⁺ from the blood.Because [EDTA-Ca²⁺] have less stability than [EDTA-Fe³⁺] (pKd[EDTA-Ca²⁺]=10.7; pKd [EDTA-Fe³⁺]=14.3) or any other heavy metals, EDTApreferentially chelates other metal ions when they are present anddisplaces calcium. In some embodiments, the chelating agent complementis a calcium salt. In some embodiments, the chelating agent complementis calcium chloride or a hydrate thereof. In other embodiments, thechelating agent complement is calcium gluconate or a hydrate thereof. Infurther embodiments, the chelating agent complement is calcium chloridedihydrate. In some instances, the calcium chloride is present at aconcentration at about 0.05 mg/mL in the morphine formulation. In otherinstances, the calcium chloride is present at a concentration at about0.053 mg/mL in the morphine formulation.

Vehicles

Liquid vehicles for the morphine formulations described herein areselected for suitability for injection as well as other qualities suchas clarity, toxicity, viscosity, compatibility with excipients, chemicalinertness, lack of color and economy. In the embodiments of the morphineformulations described herein, water for injection (e.g., USP grade) is,in certain instances, used as a vehicle for the formulation. In otherinstances, the vehicle for the morphine formulations described hereininclude solvents miscible with water. Such solvents include, but are notlimited to, ethyl alcohol, propylene glycol, glycerin, polyethyleneglycol, and polypropylene glycol. Additional known solvents that havecompatibility with the excipients and morphine are contemplated withinthe scope of embodiments.

Additional Excipients

It is contemplated with the scope of the morphine formulations describedherein to optionally comprise additional excipients including, but notlimited to, preservatives and viscosity agents. Although the morphineformulations described herein are preservative-free, the addition ofpreservatives may further prevent degradation of the active ingredient,further prevent growth of microbials and/or further increasestorage-life of the formulation. Non-limiting examples of preservativesinclude benzyl alcohol, phenol, benzoic acid, erythorbic acid, fumaricacid, malic acid, propyl gallate, BHA, BHT, parabens (methyl-, ethyl-,butyl-), cresol, vanillin, chlorobutanol, benzoates, sulfites, sorbicacid and sorbates. Viscosity agents refer to excipients that increasecompatibility and/or iso-viscosity with the physiological site ofinjection. For example, the morphine formulations described herein canbe formulated with a viscosity agent to provide compatible viscositywith that of blood. Exemplary viscosity agents include hyaluronic acid,sodium hyaluronate, polyethylene glycol, chitosan, fucans, copolymers ofpolysaccharides with degradable polymers, gelatin, starch, cellulose,cellulose derivatives, glycerol and the like. In some embodiments, themorphine formulations described herein optionally comprise apreservative. In other embodiments, the morphine formulations describedherein optionally comprise viscosity agent.

It is further contemplated that the morphine formulations describedherein, in some embodiments, are suitable for oral administration.Morphine formulations for oral administration contain, in someembodiments, additional excipients to enhance the palatability of theformulation. These include but are not limited to sweetening agents orsweeteners, flavorants, bitter taste masking agents, and colorants.

Sweeteners or sweetening agents include any compounds that provide asweet taste. This includes natural and synthetic sugars, natural andartificial sweeteners, natural extracts and any material that initiatesa sweet sensation in a subject. In some embodiments, the morphineformulations described herein described herein comprise a sweetener.Sugars illustratively include glucose, fructose, sucrose, xylitol,tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenatedisomaltulose), lactitol, sorbitol, mannitol, erythritol, trehalose,maltodextrin, polydextrose, and the like. Other sweetenersillustratively include glycerin, inulin, erythritol, maltol, acesulfameand salts thereof, e.g., acesulfame potassium, alitame, aspartame,neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharinsodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside,thaumatin, and the like. Sweeteners can be used in the form of crude orrefined products such as hydrogenated starch hydrolysates, maltitolsyrup, high fructose corn syrup, etc., and as branded products, e.g.,Sweet Am™ liquid (Product Code 918.003—propylene glycol, ethyl alcohol,and proprietary artificial flavor combination, Flavors of North America)and Sweet Am™ powder (Product Code 918.005—maltodextrin, sorbitol, andfructose combination and Product Code 918.010—water, propylene glycol,sorbitol, fructose, and proprietary natural and artificial flavorcombination, Flavors of North America), ProSweet™ (1-10% proprietaryplant/vegetable extract and 90-99% dextrose combination, ViriginiaDare), Maltisweet™ (maltitol solution, Ingredion) and Sorbo™ (sorbitoland sorbitol/xylitol solution, SPI Polyols), Invertose™ (high fructosecorn syrup, Ingredion) and Ora-Sweet® sugar-free flavored syrup (PaddockLaboratories, Inc.). Sweeteners can be used singly or in combinations oftwo or more. Suitable concentrations of different sweeteners can beselected based on published information, manufacturers' data sheets andby routine testing.

In another embodiment, the morphine formulations described herein fororal administration comprise a flavoring agent or flavorant to enhancethe taste or aroma of the composition for oral administration. Suitablenatural or synthetic flavoring agents can be selected from standardreference books, for example Fenaroli's Handbook of Flavor Ingredients,3rd edition (1995). Non-limiting examples of suitable natural flavors,some of which can readily be simulated with synthetic agents orcombinations thereof, include almond, anise, apple, apricot, bergamot,blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon,clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel,fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt,mandarin, molasses, nutmeg, orange, peach, pear, peppermint, pineapple,raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla,wintergreen, etc. Also useful, particularly where the formulation isintended primarily for pediatric use, is tutti-frutti or bubblegumflavor, a compounded flavoring agent based on fruit flavors. Presentlypreferred flavoring agents include anise, cinnamon, cacao, orange,peppermint, cherry (in particular wild cherry), grape, bubblegum andvanilla. In some embodiments, the morphine formulations described hereinfor oral administration comprise a wild cherry flavoring agent.Flavoring agents can be used singly or in combinations of two or more.

Because morphine is known to have a bitter taste, in some embodiments,the morphine formulations described herein for oral administrationcomprise a bitter taste inhibiting or masking agent. Bitter tasteinhibiting or masking agents include, but are not limited to, asweetener or flavorant as described above, alkali metal salts such assodium chloride, sodium bicarbonate, potassium bicarbonate, magnesiumbicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate,sodium citrate, sodium tartrate, sodium biphosphate, sodium phosphate,potassium phosphate or magnesium trisilicate and the like.

In further embodiments, the morphine formulations described herein fororal administration comprise a coloring agent for identity and/oraesthetic purposes of the resultant liquid form. Suitable coloringagents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C RedNo. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C OrangeNo. 5, caramel, ferric oxide and mixtures thereof.

Preparation of Morphine Formulations

Preparation of the morphine formulations described herein includes anyknown pharmaceutical method. In one embodiment, the morphineformulations described are prepared by the addition of the drug and theexcipients into a formulation tank containing a liquid vehicle. The tankagitates or mixes the liquid vehicle to promote the dissolving of thevarious components into the liquid vehicle. The drug and each excipientcan be added to the tank sequentially after the prior ingredient hasdissolved. After liquid formulation is mixed, it can be further filteredto remove particulates and reduce bioburden, and provide sterility byemploying one or more additional filters (e.g., 0.22 μm). An exemplarypreparation is described in Example 4.

In an alternative embodiment, the morphine formulations described areprepared first by a direct blend method of the drug and variousexcipients as a dry powder and then subsequently reconstituted in aliquid vehicle. For example, morphine is blended along with any otherexcipients in a dry mixer or blender. In certain instances, the powdersare passed through a mesh screen prior to and/or after mixing. The dryblend is facilitated by conventional large-scale mixing equipment suchas rotating-shell mixers (e.g., drum-type, cubical shaped, double-coneand twin-shell blender), fixed-shell (ribbon) mixers, sigma-blade andplanetary paddle mixers, vertical impeller mixers and motionless mixers.The mixing is performed to blend uniformity of a powder mixture of themorphine formulations described herein. In these embodiments, mixingmethods can include all components together or incorporate certaincomponents together first with other components subsequently added.

In the preparation embodiments of the morphine formulations describedherein, the preparation is, in some instances, in an environmentcontaining an inert gas. The use of an inert gas (e.g., nitrogen, argon,CO₂, helium and the like) limit the morphine and the excipients tooxygen exposure. Liquid vehicles and other solutions are also sparged orbubbled by the inert gas to remove oxygen in the liquid. The solutionsare then filled and sealed into primary containers and, in someembodiments, secondary packaging under inert gas.

Stability of Morphine Formulations

The morphine formulations described herein are stable in various storageconditions including ambient and accelerated conditions. Stability asused herein refers to a formulation meeting all stability criteria alongits particular shelf life, as defined in the USP or equivalent monographof the drug product (for the assay of the drug substance in particular)and the current stability criteria of the ICH Q3B guidance forimpurities. All critical quality attributes need to stay in theiracceptance range throughout the formulation's shelf life. For a morphineformulation to be stable, assay of the drug substance, i.e., morphine,is in the [90.0%-110.0%] range as per USP and per ICH Q3B guidelines,all known, i.e., identified, degradation products, such aspseudomorphine, hydroxymorphine, norphine-N-oxide, and the like, as wellas unknown degradation products need to be no more than (NMT) 0.2%.Stability of the morphine formulations described herein is assessed byHPLC, UPLC or any other known analytical method.

In some embodiments, the morphine formulations described herein arestable in ambient conditions (e.g., 25° C./60% RH) for at least 6months, at least 8 months, at least 10 months, at least 12 months, or atleast 24 months. In certain instances, the morphine formulationsdescribed herein are stable in ambient conditions for at least 12months. In certain instances, the morphine formulations described hereinare stable in ambient conditions for at least 24 months. In otherembodiments, the morphine formulations described herein are stable inintermediate conditions (e.g., 30° C./65% RH) for at least 4 months, atleast 5 months, at least 6 months, at least 9 months, or at least 12months. In certain instances, the morphine formulations described hereinare stable in intermediate conditions for at least 6 months. In certaininstances, the morphine formulations described herein are stable inintermediate conditions for at least 12 months. In further embodiments,the morphine formulations described herein are stable in acceleratedconditions (e.g., 40° C./75% RH) for at least 1 month, at least 2months, at least 3 months, at least 4 months, at least 5 months, or atleast 6 months. In certain instances, the morphine formulationsdescribed herein are stable in accelerated conditions for at least 3months. In certain instances, the morphine formulations described hereinare stable in accelerated conditions for at least 6 months. In yetfurther embodiments, the morphine formulations described herein arestable in 80° C. test conditions for at least 10 days, at least 12 days,or at least 14 days. In certain instances, the morphine formulationsdescribed herein are stable in 80° C. test conditions for at least 14days. In the stability embodiments of this paragraph, the morphineformulations are stored without any oxygen barrier packaging, i.e., themorphine formulations are manufactured and filled under nitrogen inoxygen permeable containers.

When the morphine formulations described herein are stored in oxygenbarrier packaging, the stability is improved. In some embodiments wheremorphine formulations described herein are stored in oxygen barrierpackaging, the morphine formulations are stable in ambient conditions(e.g., 25° C./60% RH) for at least 12 months, at least 15 months, atleast 18 months, or at least 24 months. In certain instances, themorphine formulations stored in oxygen barrier packaging are stable inambient conditions for at least 24 months. In other embodiments wheremorphine formulations described herein are stored in oxygen barrierpackaging, the morphine formulations are stable in intermediateconditions (e.g., 30° C./65% RH) for at least 6 months, at least 8months, at least 10 months or at least 12 months. In certain instances,the morphine formulations stored in oxygen barrier packaging are stablein intermediate conditions for at least 12 months. In furtherembodiments where morphine formulations described herein are stored inoxygen barrier packaging, the morphine formulations are stable inaccelerated conditions (e.g., 40° C./75% RH) for at least 4 months, atleast 5 months, or at least 6 months. In certain instances, the morphineformulations stored in oxygen barrier packaging are stable inaccelerated conditions for at least 6 months. In yet further embodimentswhere morphine formulations described herein are stored in oxygenbarrier packaging, the morphine formulations are stable in 80° C. testconditions for at least 10 days, at least 12 days, or at least 14 days.In certain instances, the morphine formulations stored in oxygen barrierpackaging are stable in 80° C. test conditions for at least 14 days.

In some embodiments, the morphine formulations described herein storedin ambient conditions (e.g., 25° C./60% RH) have a pseudomorphineimpurity not more than or equal to about 0.2% for at least 6 months, atleast 8 months, at least 10 months, or at least 12 months of storage. Incertain instances, the morphine formulations described herein stored inambient conditions have a pseudomorphine impurity not more than or equalto about 0.2% for at least 12 months of storage. In other embodiments,the morphine formulations described herein stored in intermediateconditions (e.g., 30° C./65% RH) have a pseudomorphine impurity not morethan or equal to about 0.2% for at least 4 months, at least 5 months, orat least 6 months of storage. In certain instances, the morphineformulations described herein stored in intermediate conditions have apseudomorphine impurity not more than or equal to about 0.2% for atleast 6 months of storage. In further embodiments, the morphineformulations described herein stored in accelerated conditions (e.g.,40° C./75% RH) have a pseudomorphine impurity not more than or equal toabout 0.2% for at least 1 month, at least 2 months, or at least 3 monthsof storage. In certain instances, the morphine formulations describedherein stored in accelerated conditions have a pseudomorphine impuritynot more than or equal to about 0.2% for at least 3 months of storage.In the stability embodiments of this paragraph, the morphineformulations are stored without any oxygen barrier packaging, i.e., themorphine formulations are manufactured and filled under nitrogen inoxygen permeable containers.

In some embodiments, the morphine formulations described herein inoxygen barrier packaging and stored in ambient conditions (e.g., 25°C./60% RH) have a pseudomorphine impurity not more than or equal toabout 0.2% for at least 12 months, at least 15 months, at least 18months, or at least 24 months of storage. In certain instances, themorphine formulations described herein in oxygen barrier packaging andstored in ambient conditions have a pseudomorphine impurity not morethan or equal to about 0.2% for at least 24 months of storage. Incertain instances, the morphine formulations described herein in oxygenbarrier packaging and stored in ambient conditions have a pseudomorphineimpurity not more than or equal to about 0.1% for at least 24 months ofstorage. In other embodiments, the morphine formulations describedherein in oxygen barrier packaging and stored in intermediate conditions(e.g., 30° C./65% RH) have a pseudomorphine impurity not more than orequal to about 0.1% for at least 6 months, at least 8 months, at least10 months or at least 12 months of storage. In certain instances, themorphine formulations described herein in oxygen barrier packaging andstored in intermediate conditions have a pseudomorphine impurity notmore than or equal to about 0.1% for at least 12 months of storage. Infurther embodiments, the morphine formulations described herein inoxygen barrier packaging and stored in accelerated conditions (e.g., 40°C./75% RH) have a pseudomorphine impurity not more than or equal toabout 0.1% for at least 4 months, at least 5 months, or at least 6months of storage. In certain instances, the morphine formulationsdescribed herein in oxygen barrier packaging and stored in acceleratedconditions have a pseudomorphine impurity not more than or equal toabout 0.1% for at least 6 months of storage.

In some embodiments, the morphine formulations described herein storedin ambient conditions (e.g., 25° C./60% RH) have a total impurity notmore than or equal to about 0.8%, not more than or equal to about 0.7%,or not more than or equal to about 0.6% for at least 6 months, at least8 months, at least 10 months, or at least 12 months of storage. Incertain instances, the morphine formulations described herein stored inambient conditions have a total impurity not more than or equal to about0.8% for at least 12 months of storage. In other embodiments, themorphine formulations described herein stored in intermediate conditions(e.g., 30° C./65% RH) have a total impurity not more than or equal toabout 0.4% or not more than or equal to about 0.3% for at least 4months, at least 5 months, or at least 6 months of storage. In certaininstances, the morphine formulations described herein stored inintermediate conditions have a total impurity not more than or equal toabout 0.4% for at least 6 months of storage. In further embodiments, themorphine formulations described herein stored in accelerated conditions(e.g., 40° C./75% RH) have a total impurity not more than or equal toabout 0.5% or not more than or equal to about 0.4% for at least 1 month,at least 2 months, or at least 3 months of storage. In certaininstances, the morphine formulations described herein stored inaccelerated conditions have a total impurity not more than or equal toabout 0.5% for at least 3 months of storage. In the stabilityembodiments of this paragraph, the morphine formulations are storedwithout any oxygen barrier packaging, i.e., the morphine formulationsare manufactured and filled under nitrogen in oxygen permeablecontainers.

In some embodiments, the morphine formulations described herein inoxygen barrier packaging and stored in ambient conditions (e.g., 25°C./60% RH) have a total impurity not more than or equal to about 1.5%,not more than or equal to about 1.2%, or not more than or equal to about1.0% for at least 12 months, at least 15 months, at least 18 months, orat least 24 months of storage. In certain instances, the morphineformulations described herein in oxygen barrier packaging and stored inambient conditions have a total impurity not more than or equal to about1.5% for at least 24 months of storage. In certain instances, themorphine formulations described herein in oxygen barrier packaging andstored in ambient conditions have a total impurity not more than orequal to about 1.0% for at least 24 months of storage. In otherembodiments, the morphine formulations described herein in oxygenbarrier packaging and stored in intermediate conditions (e.g., 30°C./65% RH) have a total impurity not more than or equal to about 0.5% ornot more than or equal to about 0.4% for at least 6 months, at least 8months, at least 10 months or at least 12 months of storage. In certaininstances, the morphine formulations described herein in oxygen barrierpackaging and stored in intermediate conditions have a total impuritynot more than or equal to about 0.4% for at least 12 months of storage.In further embodiments, the morphine formulations described herein inoxygen barrier packaging and stored in accelerated conditions (e.g., 40°C./75% RH) have a total impurity not more than or equal to about 0.5%,not more than or equal to about 0.3% or not more than or equal to about0.2% for at least 4 months, at least 5 months, or at least 6 months ofstorage. In certain instances, the morphine formulations describedherein in oxygen barrier packaging and stored in accelerated conditionshave a total impurity not more than or equal to about 0.5% for at least6 months of storage.

Methods

Provided herein, in one aspect, are methods of treatment comprisingadministration of the morphine formulations described herein to asubject. In some embodiments, the morphine formulations described hereintreat, manage or reduce pain in a subject. Pain as used herein includesboth moderate to severe pain and gradations thereof as well as acute andchronic pain. Pain can be caused by a disease (e.g., cancer), injury, ormedical procedure (e.g., surgery). Pain intensity can be measured by asubject's self reporting, observations on behavior or activity and/orphysiological data. Self reporting on pain includes measurement via apain scale. For example, a simple pain scale may include such values as0=no pain; 1-3=mild pain that may interfere with daily activities;4-6=moderate pain that interferes with daily activities; and 7-10=severepain that disables daily activities.

In certain instances, the morphine formulations described herein treat,manage or reduce moderate to severe pain in a subject. In the morphineformulations described herein treat, manage or reduce moderate pain in asubject. In other instances, the morphine formulations described hereintreat, manage or reduce severe pain in a subject. In further instances,the morphine formulations described herein treat, manage or reduce acuteor chronic pain in a subject.

In further embodiments, the morphine formulations described hereininduce anesthesia in a subject preparing for or undergoing surgery. Inyet further embodiments, the morphine formulations described hereintreat acute pulmonary edema.

In another aspect, the morphine formulations described herein reduceadverse effects of a injectable morphine pharmaceutical formulationcomprising a chelating agent such as EDTA. In some embodiments morphineformulations described herein comprise a complement to the chelatingagent (e.g., calcium chloride), the effects of the chelating agent arediminished or dampened. This is advantageous in that the morphineformulations described herein have reduced side effects of chelatingagents including impairment of blood coagulation, calcium metabolism,calcium signal transduction. The morphine formulations described hereinare also suitable for subjects that have hypocalcaemia. In someembodiments, the morphine formulations described herein are administeredto subjects having hypocalcaemia.

Dosing and Administration

Administration of a morphine formulation described herein is at a dosagedescribed herein or at other dose levels and compositions determined andcontemplated by a medical practitioner. Factors that may affect the doseand administration of a morphine formulation described herein include:the total daily dose, potency and specific characteristics of the opioidthe subject has previously taken; the subject's degree of opioidtolerance; the general condition and medical status of the subject;concurrent medications; type and severity of the subject's pain; andrisk factors and prior history for abuse and addiction.

In some embodiments, the morphine formulations described herein areprovided at a dose per administration from about 0.5 mg to about 15 mg,from about 1 mg to about 12 mg, or from about 2 to about 10 mg ofmorphine. In certain embodiments, the morphine formulations describedherein are provided at a dose per administration of about 0.5 mg, about1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg,about 13 mg, about 14 mg, about 15 mg of morphine, or any amount betweentherein. In certain instances, the morphine formulations describedherein are provided at a dose per administration of about 2 mg. Incertain instances, the morphine formulations described herein areprovided at a dose per administration of about 4 mg. In certaininstances, the morphine formulations described herein are provided at adose per administration of about 5 mg. In certain instances, themorphine formulations described herein are provided at a dose peradministration of about 8 mg. In certain instances, the morphineformulations described herein are provided at a dose per administrationof about 10 mg.

In other embodiments, the morphine formulations described herein areprovided at a dose per administration from about 0.01 mg/kg to about 0.2mg/kg morphine per body weight in a subject, from about 0.02 mg/kg toabout 0.17 mg/kg morphine per body weight in a subject, or from about0.03 mg/kg to about 0.14 mg/kg morphine per body weight in a subject.

In further embodiments, the morphine formulations described herein areprovided at a dose sufficient to manage or relieve pain in a subject. Inother embodiments, the morphine formulations described herein areprovided at a dose sufficient to induce anesthesia in a subject. In yetother embodiments, the morphine formulations described herein areprovided at a dose sufficient to treat or mange acute pulmonary edema ina subject.

The dosages of the morphine formulations described herein areadministered, in some embodiments, once per day. In other embodiments,dosages are administered b.i.d., t.i.d., q.i.d., or the like oraccording to the judgment of the health practitioner. The dosages of themorphine formulations described herein can be administered intravenouslyor intramuscularly by injection. In some embodiments, the morphineformulations described herein are administered intravenously. In otherembodiments, the morphine formulations described herein are administeredintramuscularly.

Because prolonged administration of morphine has potential for addictionor overdose, the administration of the morphine formulations describedherein may be temporarily suspended for a certain length of time (i.e.,a “drug holiday”). In specific embodiments, the length of the drugholiday is, by way of example only, between 2 days and 6 months,including 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days and 180 days. Alternatively, the morphineformulations described herein, in some embodiments, are rotated out aspart of an opioid rotation program. In an opioid rotation,administration of the morphine formulations described herein issuspended and an equianalgesic dose of another opioid is administered inits place. See Fine P G, et al., J Pain Symptom Manage. 2009;38(3):418-425. Other opioids contemplated for a rotation, include butare not limited to, hydromorphone, oxycodone, oxymorphone, fentanyl,tramadol, sufentanil and the like.

The morphine formulations described herein are suitable for parenteralor oral administration. Parenteral administration includes injectionsvia intravenous, intramuscular, subcutaneous, intradermal, intraspinal,intra-articular, and the like. In some embodiments, the morphineformulations described herein are administered by injection. In certaininstances, the injection is intravenous. In certain instances, theinjection is intramuscular. In certain instances, the injection issubcutaneous. In other embodiments, the morphine formulations describedherein are administered orally as an oral solution.

Further Combinations

The treatment, management or reduction of certain conditions (e.g.,pain) in a subject with a morphine formulation described hereinencompasses additional therapies and treatment regimens with otheragents in some embodiments. Such additional therapies and treatmentregimens can include another therapy, e.g., additional analgesics suchas other opioids (e.g., “opioid rotation”). Alternatively, in otherembodiments, additional therapies and treatment regimens include otheragents such as a chemotherapy used to treat the underlying disease orcondition or to reduce or prevent a side effect from the morphineformulation in the therapy.

Packaging for Morphine Formulations Primary Packaging

Various types of containers (i.e., primary packaging) are suitable forthe containment of the morphine formulations described herein. Examplesof such containers include, without limitation, vials, syringes,ampoules, bottles, cartridges, carpules and intravenous bags or pouches.In some embodiments, the morphine formulations described herein arepackaged or filled in a container selected from a vial, syringe,ampoule, bottle, cartridge, carpule and a bag.

Vials for the containment of the morphine formulations described hereingenerally have open mouths which are normally closed with an elastomerclosure through which a hollow needle may be passed and via which liquidmay be introduced or removed from the vial. Vials are typically made oftype I glass or may be made of plastic such as PET. Suitable elastomersfor such closures include, for example, vulcanized elastomers andstyrenic block copolymer thermoplastic elastomers, but also naturalrubber, acrylate-butadiene rubber, cis-polybutadiene, chloro orbromobutyl rubber, chlorinated polyethylene elastomers, polyalkyleneoxide polymers, ethylene vinyl acetate, fluorosilicone rubbers,hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymers,butyl rubbers, polyisobutene, synthetic polyisoprene rubber, siliconerubbers, styrene-butadiene rubbers, tetrafluoroethylene propylenecopolymers, thermoplastic-copolyesters, thermo-plastic elastomers, orthe like or a combination thereof.

Syringes generally comprise a cylindrical barrel, often made of glassbut more recently have been made of plastic materials, for example,cyclic olefin polymers or acrylonitrile butadiene styrene (ABS),polycarbonate (PC), polyoxymethylene (POM), polystyrene (PS),polybutylene terephthalate (PBT), polypropylene (PP), polyethylene (PE),polyamide (PA), thermoplastic elastomer (TPE) and their combinations.The barrels of such syringes are operated with an elastomer plungerwhich can be urged along the barrel to eject liquid content via anozzle. Suitable elastomers for such plungers may be based on the samethermoplastic elastomers as mentioned above for vial closures. Ampoulesare a type of sealed glass vial which are generally opened by snappingoff the neck or the top of the ampoule. Cartridges and carpules arespecialized containers that are inserted into a drug delivery device(e.g. syringe or autoinjector). Finally, intravenous bags and pouchesare typically used for infusion therapy or multiple dose administration.The bags and pouches are made from materials that have gas barrierproperties.

For the more rigid containers, glass as provides various benefits. Glassis generally considered to not be permeable to moisture and gaspermeation. An alternative group of materials, cyclic olefin polymers,polypropylene or polyethylene terephthalate are suitable for thecontainers as they typically have less breakage concerns as compared toglass and still exhibit good transparency. These materials includecyclic olefin copolymers such as Topas™ polymer (Topas Advanced PolymersGmbH) and cyclic olefin homopolymers such as Crystal Zenith™ polymer(Daikyo).

As morphine has sensitivity to light, the primary packaging containershould have light barrier properties. Exemplary glass or plasticcontainers for the morphine formulations described herein are amber oropaque to light. A primary packaging made of transparent materials mayalso be suitable provided it is placed in secondary or tertiarypackaging materials that are opaque to light.

In one embodiment, the morphine formulations described herein arecontained in a syringe primary packaging container. Exemplary syringesfor use in the pharmaceutical packaging systems described herein includethose described in U.S. Pat. Nos. 6,196,998; 6,200,627; 6,217,550;6,743,216; 7,141,042; and 8,075,535; U.S. Pat. Appl. No. 2011/0130717;and U.S. application Ser. No. 13/622,391 each of which is incorporatedby reference for their disclosure relating to syringe assembly.

Secondary Packaging

In some embodiments, the morphine formulations in a primary packagingcontainer described herein benefit from the addition secondary packagingthat envelops the primary packaging container. The secondary packagingprovides additional barriers to elements that can degrade morphine suchas light and oxygen. Some primary packaging containers may also bedesigned to permeable to oxygen and other gases. For example, syringes,cartridges and the like can have permeable parts (e.g., syringe tip capand stoppers) to allow sterilization process with, for example, ethyleneoxide. A primary packaging container may also be permeable because it isformed of permable materials, i.e., a plastic that is not impermeable togases. Thus, a primary packaging container with a gas permeablecomponent may cause the morphine formulations herein to degrade byallowing oxygen to permeate inside the container. As shown in Example 5,this degradation can lead to unacceptable levels.

It is therefore contemplated that the morphine formulations describeherein comprise a secondary packaging in addition to the primarypackaging container. Secondary packaging includes any container thatreceives the primary packaging container (e.g., a box, bag, blister,canister, bottle and the like) and is sealed to prevent ingress ofoxygen. The secondary packaging is made from material that has very lowpermeability to oxygen molecules (e.g., ethylene vinyl alcohol,aluminum, glass, polyamide and the like). In certain instances, thesecondary packaging further comprises an oxygen absorber inside. Theoxygen absorber functions to absorb any oxygen present in the secondarypackaging. Suitable materials for oxygen absorbers include iron, lowmolecular weight organic compounds such as ascorbic acid and sodiumascorbate and polymeric materials incorporating a resin and a catalyst.Oxygen absorbers are contemplated to be in any size or shape includingsachet, pouch, canister, lining, sticker, etc. as well as part of thesecondary packaging or primary packaging container itself. Varioussecondary packaging and oxygen absorber configurations are depicted inFIG. 11. FIG. 1 illustrates different configurations of the secondarypackaging and oxygen absorber embodiments with an oxygen absorber (2) asa sachet (FIG. 11a ) placed inside the secondary packaging (1) and underthe syringe primary packaging (3), in the lid 4 (FIG. 11b ) of secondarypackaging (1) and as a canister (FIG. 11c ) placed next to the syringeprimary packaging. Another embodiment where the oxygen absorber ispositioned directly on the syringe primary packaging is also illustrated(FIG. 11d ). An exemplary secondary packaging with an oxygen absorber isdescribed in Example 6. In another embodiment, the morphine formulationsdescribe herein in a syringe primary packaging container is placedinside a secondary packaging container.

In a further embodiment, a secondary packaging container suitable forthe morphine formulations described herein is provided which includes afirst compartment to receive a syringe barrel and second compartment toreceive a plunger rod separate and detached from the syringe barrel.With the syringe barrel received in the first compartment and theplunger rod received within the second compartment, the sealing memberof the plunger rod seals the syringe barrel and the plunger rod withinthe secondary packaging. This secondary packaging containerconfiguration allows for reduced storage space of the syringe. In thismanner, upon removal of the plunger rod and the syringe barrel from thesecondary packaging, the plunger rod can quickly and easily be securedto the syringe barrel via a stopper for delivery of a morphineformulation described herein. An exemplary syringe and secondarypackaging configuration is depicted in FIG. 12. FIG. 12 shows a syringebarrel (30) containing a morphine formulation described herein with asealing cap (20) and a flange (40) for a user's fingers received in afirst compartment portion (108) and a plunger rod (14) received in asecond compartment portion (94) of a secondary packaging (92). Theplunger rod (14) can comprise elastic fingers (160) which lock andsecure to the syringe barrel (30), a flange (66) for usability, keyslots (78) for securing the plunger rod in the second compartment of thesecondary packaging and vents (76) to allow oxygen removal with anoxygen absorber (not shown). The secondary packaging with the syringecomponents is sealed with a sealing cover (190). It is envisioned thatan oxygen absorber is in this configuration. Additional secondarypackaging configurations for the morphine formulations described hereinare found in U.S. Ser. No. 13/622,391, which is incorporated byreference for the relating to syringe and packaging assembly.

Kits and Articles of Manufacture

For the morphine formulations described herein, kits and articles ofmanufacture are also described. Such kits can comprise a secondarypackaging (e.g., carrier, package, blister or container) that iscompartmentalized to receive one or more primary packaging containers(e.g., vials, tubes, and the like as described above), each of thecontainer(s) comprising one of the separate elements to be used in amethod described herein including a morphine formulations. Suitableprimary packaging containers include, for example, vials, syringes,ampoules, bottles, cartridges, carpules and i.v. bags or pouches. Thecontainers can be formed from a variety of materials such as glass orplastic.

A kit typically may comprise one or more additional containers, eachwith one or more of various materials (such as devices) desirable from acommercial and user standpoint for a morphine formulations describedherein. Non-limiting examples of such materials include, but not limitedto, buffers, diluents, filters, needles, syringes; adaptors, wastereceptacles, and/or labels listing contents and/or instructions for use,and package inserts with instructions for use associated with a morphineformulation. A set of instructions will also typically be included.

A label can be on or associated with the secondary packaging. A labelcan be on a secondary packaging when letters, numbers or othercharacters forming the label are attached, molded or etched into thecontainer itself; a label can be associated with a secondary packagingwhen it is present within a receptacle or carrier that also holds theprimary packaging container, e.g., as a package insert. A label can beused to indicate that the contents are to be used for a specifictherapeutic application. The label can also indicate directions for useof the contents, such as in the methods described herein.

Certain Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes the standardlevel of error for the device or method being employed to determine thevalue. The use of the term “or” in the claims is used to mean “and/or”unless explicitly indicated to refer to alternatives only or thealternatives are mutually exclusive, although the disclosure supports adefinition that refers to only alternatives and to “and/or.” The terms“comprise,” “have” and “include” are open-ended linking verbs. Any formsor tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed component, structure, event or circumstance may or may notoccur, and that the description includes instances where the eventsoccurs and instances where it does not.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In some embodiments, a therapeutic agent such as morphineis directed to the treatment and/or the amelioration of, reversal of, orstabilization of the pain described herein.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. Thus, as used herein, the term “administering”, when used inconjunction with a morphine formulation, can include, but is not limitedto, providing a morphine formulation into or onto the target tissue;providing a morphine formulation systemically to a patient by, e.g.,injectable administration whereby the therapeutic reaches the targettissue or cells. “Administering” a composition may be accomplished byinjection administration or by other methods alone or in combinationwith other known techniques.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals. Asused herein, the terms “patient,” “subject” and “individual” areintended to include living organisms in which certain conditions asdescribed herein can occur. Examples include humans, monkeys, cows,sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. Ina preferred embodiment, the patient is a primate. In certainembodiments, the primate or subject is a human. In certain instances,the human is an adult. In certain instances, the human is child. Infurther instances, the human is under the age of 12 years. In certaininstances, the human is elderly. In other instances, the human is 60years of age or older. Other examples of subjects include experimentalanimals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.The experimental animal can be an animal model for a disorder thatresults in pain systems. A patient can be a human suffering from pain,in various degrees or from etiological forms.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “pharmaceutical composition” or “pharmaceutical formulation”shall mean a composition comprising at least one active ingredient,whereby the composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology). As such,a non-limiting example of a “therapeutically effective amount” or“effective amount” of a composition of the present disclosure may beused to inhibit, block, or reverse pain or to effectively induceanesthesia.

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

EXAMPLES Example 1: Oxygen and pH on Stability

A forced degradation study was performed to determine the optimum pH fora 10 mg/mL morphine sulfate injectable formulation and the impact ofoxygen on that stability.

Morphine sulfate solutions at 10 mg/mL were formulated under 2 differentconditions: one under inert conditions (nitrogen); the other under air.The pH of each solution was adjusted to 2.5, 4.0, 5.0 or 6.5. Thesolutions were individually stored in 10 mL amber vials, to preventmorphine dimerization from light. A set of samples were stored in 1) 6days in an oven at 80° C., and another set stored at 2) 4 weeks in aclimatic room at 40° C. Morphine and impurities were assessed by UPLC.FIGS. 1 to 3 depict the results of the pH and oxygen stability studies.

FIGS. 1 and 2 show that the morphine solutions prepared under inertconditions are more stable when stored at 80° C. (FIG. 1) and 40° C.(FIG. 2). FIG. 1 shows that all morphine solutions prepared under airhad higher total impurities than solutions prepared under inertconditions when stored at 80° C. for six days. With respect to pH, thesolution prepared under air at pH 2.5 showed the highest degradationwhereas the lowest degradation exhibited by the solution prepared underair at pH 5.0. In inert conditions, morphine solutions at pH 5.0 alsoexhibited the least amount of degradation at 80° C. At the 40° C.storage condition (FIG. 2), morphine solutions prepared under air alsoshowed higher total impurities than solutions prepared under inertconditions. Total impurities are also lowest when the formulation pH is5.0 in both air and inert conditions.

Morphine was also assayed via UPLC in the inerted set of morphinesolutions stored at 80° C. for six days (FIG. 3). FIG. 3 shows that,under nitrogen, the amount of morphine in the formulation is highest atpH 2.5. A significant decrease of the morphine (3% in 6 days at 80° C.)is observed at pH 6.5 and some decrease is observed at pH 5.0 and pH4.0.

The results indicate that the preparation of the solutions undernitrogen minimizes the oxidation effect and prevent an increaseddegradation. The results also indicate pH 5.0 is an optimal oneaccording to the pH and oxygen stability studies. pH 5.0 morphinesolutions showed least amount of total impurities (FIGS. 1 and 2). Whilethe morphine formulation at pH 2.5 showed less morphine decrease than atpH 5 at 80° C. (FIG. 3), it is known that a pH of 2.5 is very acidic andcan cause pain at the injection site. A formulation pH of about 5.0, asprovided herein, is closer to the physiological pH. Accordingly theformulations at pH 5.0 maintain the fine balance of having a pH closerto physiological pH (thereby reducing pain at the injection site due toa low pH, e.g., 2.5); of having lower total impurities during storage;and of having higher morphine content compared to formulations with pHof 4.0 and 6.5 (FIG. 2).

Example 2: Stability of Morphine/NaCl Formulations

The stability of morphine sulfate/NaCl formulations were evaluated underICH long term storage conditions at 25° C./65% Relative Humidity (RH)and at the accelerated storage condition of 40° C./75% RH for 6 months.Three dosage forms were tested: 2 mg/mL, 5 mg/mL and 10 mg/mL informulations according to the following table:

Strength Composition/mL 2 mg/mL 5 mg/mL 10 mg/mL Morphine 2 mg 5 mg  10mg Sodium chloride 9 mg 9 mg 8.8 mg Water for s.q.f 1 mL s.q.f 1 mLs.q.f 1 mL injection

NaCl was added to the morphine formulations at defined quantities toproduce compatible osmolality conditions. The formulations were adjustedto pH 5.0 by HCl or NaOH and filled into 1.25 mL glass syringes (Hypak™,Becton Dickinson & Co.) with a stopper. The effect of nitrogencompounding and filling was evaluated: two levels of Oxygen PartialPressure (fully inerted “N2” and partially inerted “SemiN2”) were testedalongside with a compounding and filling under air (non-inerted “Air”).The effect of steam sterilization was also studied (autoclaved “A” andnot autoclaved “NonA”).

FIG. 4 presents the levels of the total impurities content at the 2mg/mL concentration at 6 month storage at 40° C./75% RH. After 6 monthstorage at 40° C./75% RH (FIG. 4) and at 25° C./60% RH and complementarystudies at 60° C. and 80° C., it appeared that fully inerted (darksymbols) and autoclaved formulations (squares) gave the best results interms of assay stability, total and individual impurity content and pHstability.

Impurities were also individually assessed. At 6 month storage at 40°C./75% RH, the results showed individual contents greater than expectedspecifications (NMT 0.20%), mainly for pseudomorphine and an unknownimpurity (identified at the relative retention time of 0.16). Theincrease of the pseudomorphine impurity is presented in the FIG. 5 forthe 3 strengths 2, 5 and 10 mg/mL, in the fully inerted “N2” andautoclaved “A” configuration. FIG. 6 shows the increase of the RRT 0.16unknown impurity for the 3 strengths 2, 5 and 10 mg/mL, in the fullyinerted “N2” and autoclaved “A” configuration. It is contemplated thatthe formulation of those 2 degradants is promoted by oxidative and/orhydrolysis reactions.

Example 3: Stability of Various Morphine and Excipient Formulations

The results from Example 2 led to examination of additional morphineformulations. The aim was to add excipients to prevent the formation ofthese degradants that appeared out of specification in the previousexample. Thus, a forced degradation study and an accelerated stabilitystudy were performed on different new formulations of morphine sulfateformulations at 2 mg/mL, all adjusted at a pH of about 5.0 and preparedunder nitrogen. The various formulations included antioxidants(metabisulfite), buffer system (citric acid/sodium citrate) andchelating agent and complement (EDTA/CaCl2) without steam sterilization.The formulations were prepared, filled into 1.25 mL glass syringes(Hypak™, Becton Dickinson & Co.) with a stopper and were placed at 40°C./75% RH for 1 month, and 80° C. for 14 days for assessing stability.The below table summarizes the different formulations tested and theresults observed.

Composition Objective Results Sodium metabisulfite + Test antioxidantproperties decrease of pH pH adjustment of sulfites decrease of API(MPH-2-PH-NonA) increase of impurity level above specification Sodiummetabisulfite + Test antioxidant properties decrease of API sodiumcitrate/citric acid buffer of sulfites increase of impurity level(MPH-2-TAM-NonA) Test buffering and above specification antioxidantproperties of citric acid/sodium citrate Sodium metabisulfite + Testantioxidant properties decrease of API sodium citrate/citric acid + ofsulfites increase of impurity level chelating agent/complement Testbuffering and above specification (MPH-2-CHE-NonA) antioxidantproperties of citric acid/sodium citrate Test effect of chelating agenton oxidation reactions Chelating agent/complement + Test effect ofchelating increase of pH (at 80° C.) pH adjustment agent on oxidationreactions (MPH-2-PH-SS-NonA) Sodium citrate/citric acid + Test bufferingand pH and API stable chelating agent/complement antioxidant propertiesof lower level of impurities (MPH-2-TAM-SS-NonA) citric acid/sodiumcitrate Test effect of chelating agent on oxidation reactions

FIG. 7 depicts the above five formulations presented lower content ofpseudomorphine impurity after 14 days at 80° C. than the first developedformulation of Morphine/NaCl (MPH pre-stab #1). The formulations withmetabisulfite had lower pseudomorphine impurity than formulationswithout metabisulfite. However for these later formulations the level ofthe pseudomorphine impurity only reached 0.05% after 14 days at 80° C.In contrast, after 14 days at 80° C. storage condition, the totalimpurities content for the three formulations with metabisulfite was farabove the specification limit (1.5%), whereas the two formulationswithout metabisulfite presented low total impurities levels (FIG. 8).Further, while formulations containing metabisulfite, a knownantioxidant, had reduced levels of the pseudomorphine degradant, theresults show the rise of many other degradants making this metabisulfitenot suitable for improving the stability of morphine formulations.

The two non-sulfite formulations were examined on pH behavior at 80° C.As shown by the FIG. 9, the pH trend of the formulation with chelatingagent/complement and pH adjustment increases regularly over the 14 daysstorage period (+0.3%). The non-sulfite formulation with the addition ofthe buffer system (MPH-2-TAM-SS-NonA) had a more stable pH trend. Theresults show that the formulation with a buffer system (e.g., citricacid/sodium citrate) and chelating agent/complement (EDTA and calciumchloride) was the most stable formulation after 14 days at 80° C. aswell as after 1 month stability at 40° C./75% RH.

The effect of steam sterilization was also tested. It was observed inthe non-sulfite formulation having the buffer system and chelatingagent/complement (MPH-2-TAM-SS-NonA) after 14 days at 80° C., that theunknown impurity at RRT 0.16 increased at a greater rate for theautoclaved form than the non-autoclaved form. Thus, the results in thisexample suggest that autoclaving the morphine formulations is notbeneficial for stability.

Example 4: Exemplary Morphine Formulations and their Preparation

Various morphine formulations comprising a buffer system and chelatingagent/complement were prepared according to the following table.

Morphine Formulation Strength - composition per mL Material 2 mg/mL 4mg/mL 5 mg/mL 8 mg/mL 10 mg/mL Morphine 2.00 mg 4.00 mg 5.00 mg 8 mg/mL10.00 mg sulfphate pentahydrate Sodium 8.40 mg 8.40 mg 7.50 mg 7.50 mg7.50 mg chloride Sodium 2.30 mg 2.30 mg 3.45 mg 3.45 mg 3.45 mg citratedihydrate Citric Acid 0.74 mg 0.74 mg 1.11 mg 1.11 mg 1.11 mgmonohydrate Disodium 0.111 mg 0.111 mg 0.111 mg 0.111 mg 0.111 mgedetate dihydrate Calcium 0.053 mg 0.053 mg 0.053 mg 0.053 mg 0.053 mgchloride dihydrate Water for s.q.f 1 mL s.q.f 1 mL s.q.f 1 mL s.q.f 1 mLs.q.f 1 mL injection

The manufacturing process was performed under nitrogen. Formanufacturing a batch of one of the above exemplary morphineformulations, the morphine, citric acid, EDTA, calcium chloride, sodiumcitrate and sodium chloride were weighed in scaled up quantities. Aformulation tank held and agitated water for injection for compoundingthe drug and the various excipients. In the tank, each component wasindividually added and allowed to dissolve to completion (e.g., at least5 to 10 minutes) prior to the addition of the next component. Morphinewas added last. After the last addition, the tank was filled with waterfor injection at sufficient quantity for (s.q.f) the specified morphineconcentration and agitated for a period of time to homogeneity.

Content uniformity of the formulations was assessed at varioustimepoints during the final agitation at the top, middle and bottomsections of the formulation tank. The morphine formulations were thenfiltered twice through 0.22 μm filters in the manufacturing process.After the second filtration, the formulations were filled into theprimary packaging container.

Example 5: Accelerated Stability Studies with Primary and StandardSecondary Packaging

The 2 mg/mL and 10 mg/mL morphine formulations of Example 4 wereevaluated under ICH accelerated conditions at 40° C./75% RH for 6 monthsin 1.25 mL glass syringes (Hypak™) with a stopper. The syringescontaining the morphine formulations were placed in a secondary blisterpackaging of PET (polyethylene terephthalate) material with a paper lidbacking.

Results of the stability assay after 6 months storage at 40° C./75% RHrevealed that morphine content in stayed within specification parameters(NMT±10% change) for both concentrations. The assay values stayed stablein the 2 mg/mL formulation while the assay values for morphine decreasedslightly in the 10 mg/mL formulation but remained within specification.Similarly, total impurities level increased regularly over time butstayed below the specification (NMT 1.5%) for both strengths. pH valuesalso remained stable over the 6 month storage period.

With respect to individual impurities, pseudomorphine appeared after 1month storage period and increased regularly over the storage period inboth the 2 mg/mL and 10 mg/mL morphine formulations. At the end of 6months storage, this impurity passed the specification limit (NMT 0.2%).FIG. 10 depicts the presence of pseudomorphine over time in the 2 mg/mLformulation of three different batches. The pseudomorphine increase wasat a greater rate in the 10 mg/mL formulation and reached thespecification limit earlier.

Example 6: Accelerated Stability Studies with Primary and Oxygen BarrierSecondary Packaging

In order to improve the stability and shelf life of the morphineformulation of Example 4, an oxygen barrier secondary packaging wasdeveloped.

The alternative blister packaging included a thermoformed transparentshell made of a multilayer plastic film including PET and EVOH (Ethylenevinyl alcohol) (bottom web), and a heat sealed lidding material made ofpaper, PET and aluminum foil (top web). The EVOH layer of the bottom webpresents a very low permeability to oxygen molecules and the aluminumfoil is impermeable to any gas. Thus, this blister packaging restrictsthe atmospheric oxygen re-entry into the secondary packaging. Moreoveran oxygen absorber was placed inside the blister. This absorber includedan iron powder formula filled in a canister made of HDPE plastic andfunctioned to absorb any oxygen present in the secondary packaging. Theprimary packaging container, i.e., syringe, containing the morphineformulation was then placed in this alternative blister packaging.

Accelerated conditions at 40° C./75% RH for 6 months were assessedsimilarly to the previous example. For the both strengths, the morphinecontent remained stable over time and the results were compliant withthe specification (90-110%). However, with the oxygen barrier secondarypackaging configuration, the impurity profile, and more specifically thepseudomorphine impurity, were considerably improved. For the all batchesof the both strengths, the highest result of total impurities contentwere very low and stayed very far below the specification limit (NMT1.5%). The pseudomorphine content was very low and even below the limitof quantification. Results of pseudomorphine content over the 6-monthstorage period in accelerated conditions are presented in the followingtables:

2 mg/mL Morphine in Oxygen Barrier Packaging - Pseudomorphine Content T0T1 Month T2 Months T3 Months T6 Months Batch 1 ND 0.05 0.03 0.04 0.04Batch 2 ND 0.05 0.03 0.04 0.03 Batch 3 ND 0.04 0.01 0.02 0.01

10 mg/mL Morphine in Oxygen Barrier Packaging - Pseudomorphine ContentT0 T1 Month T2 Months T3 Months T6 Months Batch 1 0.02 0.02 0.03 0.030.03 Batch 2 0.02 0.02 0.02 0.03 0.02 Batch 3 0.02 0.02 0.03 0.02 0.03

As shown above, the pseudomorphine content also stayed far below thespecification limit (NMT 0.2%). The data in the example showed that thestability results obtained on the batches packaged with the oxygenbarrier packaging system show that the combination of the formulationwith the buffer and chelating systems, the manufacturing process undernitrogen and the oxygen barrier packaging ensure a good preservation ofthe morphine formulation against oxidation reactions.

Example 7: Stability Comparison of Morphine Formulations from Example 4in Oxygen Barrier Packaging with Marketed Morphine Formulation Productsof Equal Strengths

2 mg/mL, 5 mg/mL and 10 mg/mL morphine formulations were preparedaccording to Example 4 and filled into 1.25 mL glass syringes (Hypak™)with a stopper and placed into the oxygen barrier secondary packaging asdescribed in Example 6. The stability was compared with marketedmorphine formulation products of equal strengths. The testing conditionsand results are summarized in the following table:

Example 5 Example 5 Example 5 Morphine Morphine Morphine formulationformulation formulation with O2 Morphine with O2 with O2 Morphinebarrier Product barrier Morphine barrier Product packaging on Marketpackaging Product packaging on Market 2 mg/mL 5 mg/mL 5 mg/mL on Market10 mg/mL Product 2 mg/mL Tested at 6 Tested at 2 Tested at 6 10 mg/mLTested at 6 Name Tested at mos. at mos. After mos. at Tested at mos. atTest time 17 mos. 40° C./75% expiry 40° C./75% 13 mos. 40° C./75% point& Ambient RH Ambient RH Ambient RH condition conditions 24 mos atconditions 24 mos at conditions 24 mos at Expiry 24 mos at 20° C.-25° C.24 mos at 20° C.-25° C. 24 mos at 20° C.-25° C. Analytical Tests date20° C.-25° C. (proposed) 20° C.-25° C. (proposed) 20° C.-25° C.(proposed) Assay of Morphine (%) 90%-110%  101%  101%  101%  100%  104% 100% Total Impurities (%) NMT  1.7%  0.0%  0.7%  0.1%  1.1%  0.0% 1.0%Codeine Impurity NMT 0.06% 0.05% 0.06% 0.04% 0.07% 0.05% 0.2%Pseudomorphine NMT ND 0.04% 0.23% 0.03% ND 0.03% impurity 0.2% Oripavineimpurity NMT ND ND ND ND ND ND 0.2% 10-hydroxymorphine NMT 0.15% 0.04%0.04% 0.06% 0.08% 0.03% impurity 0.2% Morphine-N-oxide NMT ND ND ND0.05% ND ND 0.2% Normorphine impurity NMT ND ND ND ND ND ND 0.2%Morphinone impurity NMT ND ND 0.07% ND ND ND 0.2% Apomorphine impurityNMT ND — ND — ND ND 0.2% Unknown impurity NMT RRT (%) RRT (%) RRT (%)RRT (%) RRT (%) RRT (%) 0.2% 0.096 0.16 0.120 0.16 0.097 0.16 (0.38%)(0.02%) (0.21%) (0.03%) (0.10%) (0.02%) 0.144 1.102 0.144 (0.12%)(0.06%) (0.15%) 0.165 0.166 (0.38%) (0.19%) 0.182 0.185 (0.08%) (0.10%)0.213 0.284 (0.05%) (0.16%) 0.284 0.394 (0.15%) (0.22%) 0.391 (0.24%)0.434 (0.08%)

As shown above, the morphine formulations of Example 5 in oxygen barriersecondary packaging had much better stability than the marketed morphineproducts of comparable strengths even when the marketed morphineproducts were stored at ambient conditions while the morphineformulations of Example 5 were stored in accelerated (40° C./75% RH)conditions for 6 months which is known to be indicative of 2 years atroom temperature. The impurity assays show that all of the marketedmorphine products were out of specification limits for either totaland/or a particular impurity while the morphine formulations of Example5 were completely within specification with very low levels ofpseudomorphine (far below 0.1%) and only one unknown impurity RRT 0.16at 0.02-0.03%. The marketed morphine product at 2 mg/mL presented a highlevel of total impurities (1.7%) and was out of specification (accordingto ICH Q3B guidance) for two unknown impurities; other unknownimpurities were found significantly greater than 0.1%. The marketedmorphine product at 5 mg/mL showed unacceptable pseudomorphine andunknown impurity levels. Finally, the marketed morphine product at 10mg/mL, analyzed at about half of its shelf life had a high totalimpurity level and up to 6 unknown impurities, 4 of which being veryclose or that could be rounded to 0.2%; this indicates that this productis unlikely to meet stability acceptance criteria after two years. Theresults in this example demonstrate the increased purity and stabilityof exemplary morphine formulations described herein.

Example 8: Additional Long-Term Stability Studies of 10 mg/mL MorphineFormulations with Primary and Oxygen Barrier Secondary Packaging

Long-term stability of 10 mg/mL morphine formulations was observed inambient, intermediate and accelerated conditions. 10 mg/mL morphineformulations were prepared according to Example 4 and filled into 1.25mL glass syringes (Hypak™) with a stopper and placed into the oxygenbarrier secondary packaging as described in Example 6. The packagedsyringes containing the 10 mg/mL morphine formulations were stored atambient conditions (25° C./60% RH) for a duration of 24 months or the24-month equivalent duration in intermediate (35° C./65% RH, for 12months) and accelerated conditions (40° C./75% RH, for six months). Atvarious points during the storage period, the morphine formulations wereassessed similarly to the previous examples.

24 Month Ambient Condition Stability Results

After 24 months storage, the morphine formulations were withinspecification. The stored formulations remained clear and colorless withno visible particles detected. The number of subvisible particles persyringe increased over time, but remained far below the specificationlimits. The pH was also stable over the storage period.

Morphine content, assayed by UPLC, ranged from 98.6%-101.0% during thestorage period and was within specification limits. The content of anyindividual impurity (e.g., codeine, pseudomorphine, oripavine,norphonine and morphinone as well as unknown umpurities) were detectedbut below the limits of quantification. These impurities as well as thesum of the impurities were therefore compliant with the impurityspecifications.

The solution remained sterile after 24 months storage at ambientconditions, confirming that the primary and oxygen barrier packagingremained unaltered after the storage period. Endotoxin content after 24months storage was also compliant with specification.

The syringe also remained functional after 24 months from expel testing.

12-Month Intermediate and Six-Month Accelerated Stability Results

Results were similar in the storage stability studies in the 12-monthintermediate and six-month accelerated stability studies. For these twoconditions, all parameters were within specification. Qualitatively,morphine formulations remained clear and colorless with no visibleparticles detected. Known and unknown impurities were compliant underthe specified limits. No significant change occurred in these twoconditions.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A pharmaceutical formulation comprising: (a)morphine, or a salt thereof, or a hydrate thereof; (b) an isotonicagent; (c) a buffering agent with anti-oxidative properties; (d) achelating agent; (e) a complement to a chelating agent; and (f) water,wherein the formulation has a pH of from about 2.5 to about 6.5.
 2. Theformulation of claim 1, wherein, the morphine, or a salt thereof, or ahydrate thereof, is selected from morphine sulfate pentahydrate,morphine hydrochloride, anhydrous morphine, morphine hydrochloride,morphine sulfate, morphine tartrate, morphine citrate, morphine acetate,morphine methobromide, morphine hydrobromide, morphine hydroiodide,morphine lactate and morphine bitartrate.
 3. The formulation of claim 1,wherein the isotonic agent is selected from sodium chloride, calciumchloride, potassium chloride, sodium bicarbonate, sodium lactate,Ringer's solution, dextrose, lactose, mannitol, glucose, glycerine,dextran, Normosol R, saline, Hartmann's solution, and mixtures andcombinations thereof.
 4. The formulation of claim 1, wherein thebuffering agent is a di-carboxylic or tri-carboxylic acid.
 5. Theformulation of claim 1, wherein the buffering agent is citric acid, isocitric acid, aconitic acid, trimesic acid, propane-1,2,3-tricarboxylicacid, fumaric acid, oxalic acid, maleic acid, malonic acid, glutaricacid, succinic acid or tartaric acid, or hydrates thereof.
 6. Theformulation of claim 1, comprising a conjugate base to the bufferingagent.
 7. The formulation of claim 1, wherein the pH is from about 4.5to about 5.5.
 8. The formulation of claim 1, wherein the pH is about 5.9. The formulation of claim 1, wherein the buffering agent is in anamount which provides a molar ratio of morphine to the buffering agentfrom about 0.4 to about 1.3.
 10. The formulation of claim 1, wherein thebuffering agent forms a buffer comprising citric acid and sodiumcitrate.
 11. The formulation of claim 1, wherein the chelating agent isselected from edetic acid, ethylene glycol tetraacetic acid,ethylenediamine, diethylene triamine pentaacetic acid, N (hydroxyethyl)ethylenediaminetriacetic acid, aminotriacetic acid,2,3-dimercapto-1-propanesulfonic acid, dimercaptosuccinic acid,dimercaprol, 1,2-bis(o-aminophenoxy)ethane N,N,N′,N′-tetraacetic acid,salts and hydrates thereof.
 12. The formulation of claim 1, wherein thecomplement to chelating agent is a calcium salt.
 13. The formulation ofclaim 1, wherein, the formulation provides a unit dose of morphine, or asalt thereof, or a hydrate thereof, in a concentration from about 2mg/mL to about 15 mg/mL.
 14. The formulation of claim 1, wherein theformulation comprises not more than about 1.5% total impuritiesfollowing storage at 25° C./60% Relative Humidity for at least 12months.
 15. The formulation of claim 1, wherein the formulationcomprises not more than about 0.2% pseudomorphine following storage at25° C./60% Relative Humidity for at least 12 months.
 16. The formulationof claim 1, wherein the formulation is stored in a glass or plasticcontainer.
 17. The formulation of claim 1, wherein the formulation isfor injectable administration.
 18. A pharmaceutical formulationcomprising: (a) morphine, or a salt thereof, or a hydrate thereof; (b)an isotonic agent; (c) a buffering agent with anti-oxidative properties;(d) a chelating agent; (e) a complement to a chelating agent; and (f)water, wherein the formulation comprises not more than about 1.5% totalimpurities following storage at 25° C./60% Relative Humidity for atleast 12 months.
 19. The pharmaceutical formulation according to claim18, wherein the formulation comprises not more than about 0.2%pseudomorphine following storage at 25° C./60% Relative Humidity for atleast 12 months.
 20. A method of reducing adverse effects of aninjectable morphine pharmaceutical formulation comprising a chelatingagent, the method comprising the addition of a complement to thechelating agent to the injectable morphine pharmaceutical formulation.